Zinc enolates stability

FIGURE 85. Schematic structures of zinc enolates stabilized by intramolecular nitrogen coordination... 

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

The Reformatsky reaction is a classical reaction in which metallic zinc, an a-haloester, and a carbonyl compound react to give a (i-hydroxyester.162 The zinc and a-haloester react to form an organozinc reagent. Because the carboxylate group can stabilize the carbanionic center, the product is essentially the zinc enolate of the dehalogenated ester.163 The enolate effects nucleophilic attack on the carbonyl group. 

The oxidative insertion of zinc into a-halo carbonyl compounds and the subsequent reaction of the zinc enolates formed with various electrophiles can either be carried out in a one-pot Barbier-type fashion or in two consecutive steps.1-3 Zinc enolates exhibit a reasonably high stability over a wide temperature range (from -78°C to above 80°C for short periods of time) compared to other metal enolates. Although it has been reported that solutions of BrZnCH2COOtBu can be stored for several days without loss in activity,5 it is generally advisable to use freshly prepared reagents in order to avoid... 

Another intermediate for which Die Is-Alder trapping provided convincing evidence is the oxy-allyl cation. This compound can be made from a,oc -dibromoketones on treatment with zinc metal. The first step is the formation of a zinc enolate (compare the Reformatsky reaction), which can be drawn in terms of the attack of zinc on oxygen or bromine. Now the other bromine can leave as an anion. It could not do so before because it was next to an electron-withdrawing carbonyl group. Now it is next to an electron-rich enolate so the cation is stabilized by conjugation. 

NATURE OF THE REFORMATSKY REAGENT /. 8J2.I Isolation and Stability of Zinc Enolates... 

According to Gaudemar and Curd, dimethoxymethane is an especially useful solvent for two-stage reactions and they report yields of 70-80% for the Reformatsky reagents derived from a variety of a-bromo esters (equation 2) however, the procedure was unsatisfactory with ethyl a-bromopropionate, methyl a-bromophenylacetate and phenyl a-bromoisobutyrate. The zinc enolates were generally used shortly after preparation and no data on their stability in this solvent were reported. 

Aldol condensations of zinc enolates under conditions of thermodynamic control are reasonably discussed in terms of the relative stability of the two chelated aldolates (19), which leads to the syn aldol, and (20), which leads to the anti aldol. If R is larger than R, the anti chelate, with R and R trans in a six-atom ring, is expected to be the more stable form. Heathcock has noted that the most common mechanism for equilibration of aldolate stereochemistry is reverse aldolization (reversal of equation 29). Aldolates obtained by reaction of an enolate with ketone substrates are expected to undergo reverse aldolization at a faster rate than those obtained with aldehyde substrates, in part for steric reasons. Similarly, aldolates derived from ketone enolates are expected to undergo reverse aldolization at a faster rate than those derived from the more basic ester or amide enolates. 

Non-stabilized zinc ester enolates (463) (Reformatsky enolates) have been reported to add to terminal alkynes (465) in the presence of nitriles RC=N, affording (467). The reaction is initiated by the Blaise reaction of (463) with the nitrile, which generates the zinc chelate (464). The latter species then adds to the alkyne (465) in a Markovnikov manner, and the resulting intermediate (466) undergoes a retro-Blaise fragmentation to afford the zinc enolate (467) and the original nitrile. When combined with aDiels-Alder reaction partner and subsequent oxidative aromatization, this sequence can serve as a one-pot de novo construction of a-arylated alkanoates. " ... 

The analogue in which carbon replaces oxygen in the enol ring should of course avoid the stability problem. The synthesis of this compound initially follows a scheme similar to that pioneered by the Corey group. Thus, acylation of the ester (7-2) with the anion from trimethyl phosphonate yields the activated phosphonate (7-3). Reaction of the yhde from that intermediate with the lactone (7-4) leads to a compound (7-5) that incorporates the lower side chain of natural prostaglandins. This is then taken on to lactone (7-6) by sequential reduction by means of zinc borohydride, removal of the biphenyl ester by saponification, and protection of the hydroxyl groups as tetrahydropyranyl ethers. 

Substitution of the acetate group at the C-3 position of the /3-sultam 105 can occur by reaction with silyl enol ethers in the presence of zinc iodide or zinc chloride. When the diazo compound is used, after desilylation with tetrabutyl-ammonium fluoride (TBAF), photochemical cyclization gives the bicyclic /3-sultam 106 as a mixture of two cis/ fra -diastereoisomers. When silyl enol ethers derived from cyclic ketones are used, the substitution product is stabilized by a retro-Michael-type reaction leading to open-chained sulfonamides 107 (Scheme 31) <1997LA1261>. 

The popularity of the Nef reaction is due in part to the ready availability of nitro compounds. Primary and secondary halides react with sodium nitrite in dimeAyl sulfoxide (DMSO) or dimethylform-amide (DMF) to give useful yields of nitro compounds. Primary amines can be oxidized to nitro compounds with potassium permanganate, m-chloroperbenzoic acitP or ozone. Chlorination of oximes with hypochlorous acid and reduction with magnesium, zinc or hydrogen/lpalladium gives secondary nitro compounds. Stabilized carbanions can be nitrated by treauitent with a nitrate ester, and enol acetates are nitrated by acetyl nitrate to give nitro ketones. ... 

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